Identification of potential SARS-CoV-2 papain-like protease inhibitors with the ability to interact with the catalytic triad

Severe acute respiratory syndrome corona virus2 (SARS-CoV-2) is responsible for the current pandemic that led to so many deaths across the globe and still has no effective medication. One attractive target is Papain-like protease (PLpro), which plays a critical role in viral replication. Several important structural features dictate access to the PLpro narrow active site, which includes a series of loops surrounding the area. As such, it is difficult for chemical compounds to fit the SARS-CoV-2 PLpro active site. This work employed a computational study to discover inhibitors that could bind to the SARS-COV-2 PLpro active site, mainly by virtual screening, molecular dynamic simulation, MMPBSA and ADMET analysis. Eight potential inhibitors were identified: carbonoperoxoic acid, Chrysophanol-9-anthrone, Adrenolutin, 1-Dehydroprogesterone, Cholest-22-ene-21-ol, Cis-13-Octadecenoic acid, Hydroxycarbonate and 1-(4-(4-Methylphenyl)-5-phenyl-1,3-oxazol-2-yl) isoquinoline, with binding scores of -4.4, -6.7, -5.9, -6.7, -7.0, -4.6, -4.5 and -5.6 kcal/mol, respectively. All these compounds interacted with critical PLpro catalytic residues and showed stable conformation in molecular dynamics simulations with significant binding energies of -12.73 kcal/mol, -10.89 kcal/mol, -7.20 kcal/mol, -16.25 kcal/mol, -19.00 kcal/mol, -5.00 kcal/mol, -13.21 kcal/mol and -12.45 kcal/mol, respectively, as revealed by MMPBSA analysis. ADMET analysis also indicated that they are safe for drug development. In this study, we identified novel compounds that interacted with the key catalytic residues of SARS-CoV-2 PLpro with the potential to be utilized for anti-Covid-19 drug development.